Diabetes is one of the most prevalent diseases in the Western world, with severe complications including hypertension and progressive renal damage, leading to end-stage renal failure. Interestingly, sex differences have been noted, with a higher occurrence of diabetes and more rapid progression of renal and cardiovascular disease in women than men. This points to the likely contribution of sex steroids in the development of diabetic nephropathy (DN) and hypertension. Despite the potential beneficial effects of estrogen in cardiovascular disease, little is known about its role in diabetes. In fact, epidemiological studies have reported that the "protective" advantage of estrogen is lost in diabetes, suggesting that estrogen and/or estrogen receptors are abnormally regulated in the diabetic state. This is confirmed in diabetic animals, in which circulating estrogen (E2)levels are decreased, and ERs have been shown to be down-regulated in many tissues. Our findings and those of others indicate that there is cross talk between three major hormonal systems, estrogen, growth hormone (GH), and angiotensin (Ang) II, which play important roles in diabetic complications. To link these concepts together, work from our lab and other investigators, indicates that estrogen normally regulates the activity of the RAS in the vasculature and the kidney via downregulation of the ATtR and circulating Ang II. Our work suggests that this tonic inhibition of the ATIR appears to override the A TIR-stimulatory effects of Ang II and GH, and may be the underlying mechanism for estrogen's protective effects in the female. However, in diabetic animals, the decrease in circulating estrogen and down-regulation of ERs would release the inhibition of the AT1Rs, and allow enhanced action of Ang II and GH via AT1Rs. We hypothesize that there is a decrease in renal estrogen receptors in the diabetic state, and the loss of estrogen's tonic inhibitory effects on renal A TIRs (via decreased ER) allows enhanced action of Ang II and GH in the female animal, leading to exacerbation and progression of diabetic renal and cardiovascular disease. We will use whole animal, cell, molecular, and morphologic studies to address this hypothesis. Our specific aims are to 1) establish the GH- and Ang /I-related mechanisms that regulate renal E2 receptors in normal female and male animals; 2) to determine the physiological significance of the interaction between E2, GH, and Ang II in the pathogenesis of diabetes-induced renal disease; and 3) establish the mechanisms by which the higher concentrations of Ang II and GH with hyperglycemia leads to altered cellular function that characterizes diabetes. Novel aspects of this proposal include; the hypothesis that the renal ERs provide tonic inhibition of renal AT1Rs, and this helps regulate the effects of Ang II in the female; the proposed interactions between E2, GH and Ang II in regulating both ER and AT1Rs; and the use of the new model of diabetes, the GH replaced, STZ rat, which is ideal for this work. These studies will center on the mechanisms that are dysregulated in the female, leading to an increased incidence and progression of diabetes. Understanding the sex-related mechanisms will help define specific therapeutic interventions.